Histoplasma capsulatum is a fungus that has a distribution in temperate climates, especially in endemic areas of North, South, and Central America (Scheel et al., 2009; Daher et al., 2007; Huber et al., 2008; Baddley et al., 2011; Chu et al., 2006). Histoplasmosis is the most common endemic mycosis in the U.S. Infection occurs after inhalation exposure to microconidia from mold that grows in soil. After acquisition into the lungs, conidia are ingested by resident and recruited phagocytes, which migrate to resident lymphatic tissue and organs of the reticuloendothelial system (RES). The intracellular yeast form of the organism can remain viable inside macrophages, but robust interferon-gamma (INFγ) Th1 immunity assists to keep disease in check, with development of granulomatous inflammation. Hence, infection is usually asymptomatic or subclinical in subjects who have intact cellular immunity. However, in subjects in whom immunity is impaired, such as subjects with transplanted organs or TNFα inhibition, infection can occur after acquisition and with reactivation of latent infection. Such an infection can be severe or fatal.
Studies performed in the 1960s measured skin-test hypersensitivity to assess exposure (Furcolow, 1963), with results suggesting high rates of latent infection in healthy subjects, with rates some areas exceeding 80%. Establishing the diagnosis of infection and disease, however, remains difficult today. No commercial tests are available to detect skin hypersensitivity responses. Even with active, disseminated disease, diagnosis is difficult, and clinicians are often misled both by the variety of clinical manifestations and the low sensitivity of diagnostic assays. Sensitivity of organism culture and cytopathology is very low; hence, immunodiagnostics have become important.
Reference laboratories currently provide tests to measure circulating antibodies (Ab) and/or antigens (Ag), but the performance of these tests is limited, with low sensitivity of Ab detection, and Ag cross-reactivity with other fungi. With diagnostic limitations, outcomes can be poor. Also, the inability to reliably detect latent infection has limited development of strategies to prevent progression of disease in settings of impending immune suppression, as is done with other latent infections, such as tuberculosis (TB).
The pathogenesis of histoplasmosis and TB are similar. Both infections develop after inhaled exposure of an organism that remains latent in host phagocytes and kept dormant with T-cell dependent host response. Clinical syndromes are almost exactly alike. For years, skin tests to measure delayed type sensitivity to Mycobacterial antigens (Purified Protein Derivative; PPD) were the backbone for identifying prior infection. More recently, T-cell diagnostic assays have revolutionized TB diagnostics, with two commercially available interferon-gamma release assays (IGRAs) now proving to have improved sensitivity and specificity compared to skin testing. Also, these tests allow interpretation of more quantitative Type-1 responses, potentially providing prognostic implications. Being able to uncover latent infection better has enabled therapeutic strategies to prevent TB in subjects with impending immune suppression, such as with organ transplant and TNF-α inhibition. Because of the difficulties of identifying latent infection with pathogenic fungi, therapeutic strategies to prevent active pathogenic fungi infection are not available.
Although infection is typically self-limited in subjects who can mount effective Type-1 responses, severe disease occurs when immune suppressed subjects become acutely infected, and when the host response fails to keep the organism in check, such as with aging, progressive HIV infection, after treatment with biological inhibitors of TNF-α and after transplant (Wood et al., 2003). These are situations in which it would be beneficial to reliably predict latent infection to devise prevention strategies. Instead, now, infection is usually fairly widespread when it is recognized in the subject. A recent retrospective cohort study of documented histoplasmosis in U.S. organ transplant patients noted that most disease was diagnosed after dissemination and associated with a mortality rate of 10% (Assi et al.).